Bile acids have received considerable interest in the drug delivery research due to their peculiar physicochemical properties and biocompatibility. The main advantage of bile acids as drug absorption enhancers is their ability to act as both drug solubilizing and permeation-modifying agents. Therefore, bile acids may improve bioavailability of drugs whose absorption-limiting factors include either poor aqueous solubility or low membrane permeability. Besides, bile acids may withstand the gastrointestinal impediments and aid in the transporter-mediated absorption of physically complexed or chemically conjugated drug molecules. These biomolecules may increase the drug bioavailability also at submicellar levels by increasing the solubility and dissolution rate of non-polar drugs or through the partition into the membrane and increase of membrane fluidity and permeability. Most bile acid-induced effects are mediated by the nuclear receptors that activate transcriptional networks, which then affect the expression of a number of target genes, including those for membrane transport proteins, affecting the bioavailability of a number of drugs. Besides micellar solubilization, there are many other types of interactions between bile acids and drug molecules, which can influence the drug transport across the biological membranes. Most common drug-bile salt interaction is ion-pairing and the formed complexes may have either higher or lower polarity compared to the drug molecule itself. Furthermore, the hydroxyl and carboxyl groups of bile acids can be utilized for the covalent conjugation of drugs, which changes their physicochemical and pharmacokinetic properties. Bile acids can be utilized in the formulation of conventional dosage forms, but also of novel micellar, vesicular and polymer-based therapeutic systems. The availability of bile acids, along with their simple derivatization procedures, turn them into attractive building blocks for the design of novel pharmaceutical formulations and systems for the delivery of drugs, biomolecules and vaccines. Although toxic properties of hydrophobic bile acids have been described, their side effects are mostly produced when present in supraphysiological concentrations. Besides, minor structural modifications of natural bile acids may lead to the creation of bile acid derivatives with the reduced toxicity and preserved absorption-enhancing activity.

Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment. In addition, there is a significant effort to unveil some specific properties of bile acids relevant to their intrinsic potency and selectivity for particular receptors and to design novel modulators of these receptors with improved pharmacokinetic and pharmacodynamic profiles. This resulted in synthesis of few semi-synthetic bile acids derivatives such as 6α-ethyl-chenodeoxycholic acid (obeticholic acid, OCA), norursodeoxycholic acid (norUDCA), and 12-monoketocholic acid (12-MKC) that are proven to have positive effect in metabolic and hepato-biliary disorders. This review presents an overview of the current knowledge related to bile acids implications in glucose, lipid and energy metabolism, as well as a potential application of bile acids in metabolic syndrome treatment with future perspectives.

The gut–brain axis is a bidirectional communication network in which gut microbiota and their metabolites influence central nervous system (CNS) function. Among these metabolites, bile acids have emerged as key signaling molecules that modulate metabolic and neuroendocrine pathways. Microbiota-mediated modifications of bile acid composition affect receptors such as farnesoid X receptor (FXR)and Takeda G protein-coupled receptor 5 (TGR5), thereby influencing neuronal activity, appetite control, glucose metabolism, and energy balance. Emerging evidence indicates that bile acids act both directly on the CNS and indirectly via endocrine and immune mediators, linking microbial metabolism to brain function. By integrating microbiological, metabolic, and neuroendocrine perspectives, bile acids can be viewed as critical messengers in the communication between the gut microbiota and the CNS. The purpose of this review is thus to synthesize current mechanisms underlying these interactions and highlight their therapeutic potential in metabolic and neurodegenerative disorders.

Nano-drug delivery systems provide targeted solutions for addressing various drug delivery challenges, leveraging nanotechnology to enhance drug solubility and permeability. Liposomes, explored for several decades, face hurdles, especially in oral delivery. Bile-acid stabilized vesicles (bilosomes) are flexible lipid vesicles, composed of phospholipids or other surfactants, along with amphiphilic bile salts, and they show superior stability and pharmacokinetic behavior in comparison to conventional vesicular systems (liposomes and niosomes). Bilosomes enhance skin penetration, fluidize the stratum corneum, and improve drug stability. In oral applications, bilosomes overcome drawbacks, offering improved bioavailability, controlled release, and reduced side effects. Vaccines using bilosomes demonstrate efficacy, and bilosomes for intranasal, inhalation, ocular, and buccal applications enhance drug delivery, offering targeted, efficient, and controlled activities. Formulations vary based on active substances and optimization techniques, showcasing the versatility and potential of bilosomes across diverse drug delivery routes. Therefore, the aim of this comprehensive review was to critically explore the state-of-the-art of bilosomes in drug delivery and potential therapeutic applications.